The Broken-Heart syndrome (Takotsubo syndrome)

Takotsubo syndrome (TTS)/ Takotsubo cardiomyopathy/ stress-induced cardiomyopathy/ broken-heart syndrome is an acute cardiac disease characterized by chest pain, elevation of biomarkers(e.g., cardiac troponin and brain natriuretic peptide (BNP), and  ischaemic electrocardiographic (ECG) changes due to emotional or physical stress. It was first described in Japan in 1990- 1991. It is associated with transient  left ventricular dysfunction due to acute akinesia/hypokinesia of the mid and apical segments (contractile dysfunction) of the left ventricle and hyperkinesia of the basal segment (overcontraction). Other abnormalities have been described as well.

Takotsubo (tako = octopus, tsubo = a pot)  is a traditional Japanese round pot with narrow neck used as an octopus trap by the fishermen similar in shape to the apical ballooning of left cardiac chamber that occur in the stress-induced cardiomyopathy (Takotsubo cardiomyopathy). 

About 1-3% of patients presenting with suspected Acute coronary syndrome (ACS) also have TTS. About 5-6% of female patients presenting with suspected ACS, actually have TTS. TTS is more common in women with 90% of patients being postmenopausal. Most cases are underdiagnosed and missed which affects its prevalence. In the United States, about 85%-90% of patients are women between the ages 65-70 according to studies. However, TTS have been described also in children and even  premature neonates. Younger patients are more likely to be males.

Higher prevalence of TTS among Caucasians was detected in the U.S. Higher frequency of in-hospital complications (e.g., respiratory failure, stroke) was found in African-American TTS patients. TTS is highly associated with neoplasms whether active cancer or a history of malignancy and could be associated with more complications in TTS. Note that subclinical TTS commonly is not detected.

The higher rates of stress experienced by individuals over the past years, especially following the COVID-19 pandemic, have led to an increase in the prevalence of TTS by 3 to 4 times. The annual recurrence rate is about 1.5%, with recurrence incidence 1.2% at 6 months and 5% at 6 years according to some studies. 

The expression of some genes including BAG3 and GRK-5 may be associated with TTS.

The cardioprotective action of estrogen occurs through decreasing sensitivity of Beta-1 adrenergic receptors (β1ARs) to ischemic injury, decreasing intracellular calcium levels while increasing its clearance, inhibition of apoptosis (a programmed cell death to eliminate damaged or unnecessary cells) of the cardiac myocytes, and inhibition of NF-κB activation (Nuclear factor kappa-light-chain-enhancer of activated B cells is a protein complex plays important role in controlling DNA transcription, immune responses, and cell survival). Other cardioprotective function proved by research is through increasing Atrial Natriuretic Peptide (ANP) (it is a cardiac hormone protecting the heart by decreasing blood volume and the load on the heart, dilating blood vessels, and blocking stress hormones) and  heat shock protein 704 (HSP704 ) (through inhibiting cellular apoptosis, reducing oxidative stress, and regulating signaling pathways during ischemic injury). Research also found that estrogen inhibits calcineurin (a calcium- and calmodulin-dependent enzyme activates T-cells in the immune system), therefore prevents cardiac hypertrophy.

Low estrogen levels occurring postmenopausal lead to imbalance between vasoconstricting and vasodilating factors resulting in microvascular coronary artery spasm. This may explain the increased prevalence among postmenopausal women. It was found that the risk of TTS occurrence is 5-fold increased in women over 55 years of age compared to younger ages.

Depression and anxiety are commonly associated with TTS.  A study by El-Sayed et al. showed that TTS is highly associated with anxiety and mood disorders. In response to stress, changes in the HPA axis are related to decreased hippocampal volume and gray matter loss (Anatomic alterations occur in the cerebrum) that have been connected to depression and chronic stress.  In depression, an exaggerated norepinephrine response to emotional stress is observed while in anxiety, decreased reabsorption of norepinephrine occurs. Another study by Corrigan, Frank E 3rd et al. found that susceptibility to TTS is increased if associated with underlying psychiatric disorders or their exacerbation, after exposure to a severe stress. Some Central nervous system (CNS) conditions are associated with TTS such as seizures, subarachnoid haemorrhage, and ischaemic stroke due to brain-heart interactions.

Stress whether emotional or physical (e.g.,  illness or death of a loved one, excessive fear or anger or grief, earthquakes and aftershocks, car accidents, cancers,  job loss, bad financial news, vigorous exercise, alcohol/opiate withdrawal, divorce, giving birth, hyperthyroidism, seizures, strokes, infectious diseases, SARS-CoV-2 infection,  asthma attacks, surgery, postoperative pain, and anaesthesia). β-adrenoreceptor (βAR) agonists such as salbutamol may also trigger TTS. The disease is named Broken heart syndrome and it is triggered by acute emotional stress.

Sudden emotional or physical stress causes an increased level of catecholamine leading to left ventricular dysfunction. A study found that about 39% of TTS experienced emotional stress and about 35% experienced physical stress. 

A systematic review found that risk factors associated with TTS in the absence of any coronary artery disease are hypertension (54%), dyslipidemia (32%), psychological disorders (24%), smoking (22%), obesity (17%), diabetes (17%),  pulmonary diseases (15%), malignancies (10%), chronic kidney disease (7%), neurologic diseases (7%), and thyroid diseases (6%). 

The exact mechanism is unclear. The most accepted hypothesis is the involvement of  adrenergic cascade through the hypothalamic–pituitary–adrenal axis resulting in catecholamine rise which occurs through two phases: 

-Phase (1): activation of  hypothalamic–pituitary-adrenal axis after a physical or emotional stress is experienced..

-Phase (2): sympathetic hyperactivity leading to  myocardial dysfunction.

Cardiotoxicity of catecholamines may occur due to:

Increased release of catecholamines is usually triggered by emotional or physical stress. Compared to patients of  myocardial infarction and heart failure, serum catecholamine levels were found higher in patients of TTS and remain elevated for a longer period of time. Elevated levels of noradrenaline were found in the coronary sinus of TTS patients suggesting elevated myocardial catecholamines.

-Myocardial (neurogenic or catecholaminergic) stunning: High catecholamine levels interact with  beta-adrenergic receptors (βARs) which become more sensitive during stress, affecting inotropic function (force of cardiac muscle contraction), leading to myocardial dysfunction. Following the activation of βARs, calcium overload, production of reactive oxidative species, and mitochondrial dysfunction occur. The highest concentration of beta-adrenergic receptors is in the apical myocardium. Lower concentration of beta-adrenergic receptors present passing from the apex to the base of the heart which is supported by mammalian studies. Myocardial stunning may lead to arrhythmias and irreversible cellular injury. Despite the catecholamine toxicity to the myocardium, cardiac magnetic resonance imaging (CMR) of TTS cases showed only significant myocardial oedema with no significant fibrosis suggesting a potential recovery and only transient myocardial dysfunction.

-Microvascular spasm: Diffuse coronary vasoconstriction was observed in TTS cases. Some researchers suggest that prolonged severe  microvascular constriction leads to transient myocardial ischaemia, myocardial injury, and severe impairment of left ventricle contractility. This is combined with the effect of the sympathetic nervous system leading to increased cardiac load and eventually mismatch between cardiac supply and demand. Intracoronary adenosine has shown improvement in both epicardial and microvascular spasm according to multiple studies. TTS may be considered a variant of ACS. Spontaneous multivessel  coronary vasospasm was detected in about 5-10% of individuals. 

-Increased Afterload: Increased afterload mainly due to hypertension is another vascular hypothesis explaining TTS.

-Left ventricular outflow tract obstruction (LVOTO): LVOTO is another hypothesis as it leads to imbalance between oxygen supply and demand and in severe cases, it can lead to hypotension or cardiogenic shock. Risk factors of LVOTO include localized sigmoid septum and small left ventricle. A study found that almost 25% of TTS patients had LVOTO. This hypothesis cannot explain the involvement of the right ventricle in some cases and the apical-sparing and basal patterns seen in some TTS patients. So, LVOTO can be a complication not a cause of TTS.

Most TTS cases present as ACS in postmenopausal women after experiencing acute stress. Common symptoms include chest pain and dyspnea (shortness of breath) while physical examination may be non-specific. Most patients experience typical chest pain that is difficult to differentiate from MI.  Some patients present with heart failure symptoms like dyspnoea, orthopnoea (dyspnea on lying flat), acute pulmonary oedema or syncope. Some patients are asymptomatic with electrocardiogram or biomarker abnormalities detected incidentally. The physical examination of some patients may show diaphoresis (excessive, profuse sweating), hypotension, with clinical features of acute heart failure. Mitral regurgitation, ventricular arrhythmias, brady arrhythmias, LVOT obstruction, and cardiogenic shock may occur in some patients. TTS patients may only present with emotional or physical stress. 

-Typical (Apical) variant: representing about 80% of cases with apical ballooning,  hypokinesia, akinesia, or dyskinesia of mid-apical myocardial segments.

-Atypical variant: representing about 15-18% of cases, with  hypokinesia, akinesia, or dyskinesia of midventricular segments.

-Basal variant: representing about 2%, involving only the basal segment. 

-Focal variant: representing about 1.5% affecting anterolateral segment.

-Other variants: isolated right ventricular dysfunction or biventricular dysfunction.

Many TTS cases are missed as its presentation is similar to ACS. However, the International Takotsubo Registry established a  seven criteria-score (InterTAK Diagnostic Criteria) to differentiate TTS from ACS:

-A score of 30 points: has a predictive probability of <1% of having TTS

-A score of  >70 points: has a probability of approximately 90% of being TTS

*Electrocardiogram (ECG):

Most TTS cases have ECG changes similar to ACS in the form of ST-segment elevation followed by T-wave inversion and QT-interval prolongation with gradual resolution of T-wave inversion which can even  persist for several months. QT prolongation is likely to normalize within 48 hours. Other findings include transient Q waves and flattening T waves. The priority is to detect if the patient needs urgent coronary angiography. Some features of ECG have 91% sensitivity and 96% specificity for TTS including: absent abnormal Q waves, lack of ST-elevation in lead V1, presence of ST-elevation in AVR, and absent reciprocal changes. However, ECG may be unremarkable showing non-specific changes. 

*Cardiac biomarkers: 

Creatine kinase-myocardial band isoenzyme (CK–MB), troponin and BNP may be elevated on admission of TTS cases. Troponin peak is usually within 24 hours. Plasma B-Type natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-pro BNP) levels reflect the degree of left ventricle impairment and usually peak within 48 hours of the onset of symptoms and normalize gradually over the following months of presentation. Early BNP/troponin T, and BNP/CK-MB ratios may help distinguish TTS from ACS better than BNP alone.

*Echocardiography:

A quick, non-invasive, and the first imaging modality that can be used is Transthoracic echocardiography (TTE) to detect the global function of the LV, the regional wall motion abnormalities (RWMA) observed in the typical and atypical variants of TTS, involvement of right ventricle, dynamic LV outflow obstruction (LVOTO), mitral regurgitation, thrombus formation in a dysfunctional LV apex, and ventricular rupture in rare cases. The regional wall motion abnormality extends beyond one territory and is not limited to a single epicardial coronary artery in most cases that could help differentiate TTS from MI. Acute phase of TTS typically shows  akinetic or dyskinetic apical and mid ventricular wall motion abnormalities “Apical Ballooning” compared to the basal segments. 

With resolution of myocardial stunning, LV function is improved. About 50% of patients undergo early recovery with absence of RWMA within 10 days of TTS onset and the other half undergo delayed recovery nearly over 2 months. On average, LV function improvement is detected on day 18.  However,  close follow-up with serial TTE is required due to risk of complications and mortality. 

*Cardiac magnetic resonance (CMR):

CMR can be helpful in the acute phase of TTS and to identify any complication. CMR can detect RWMA, RV function, and global LV function. CMR can be used to exclude infectious myocarditis. CMR has higher special resolution than TTE. CMR through T2-weighted sequences can be used to assess reversible myocardial inflammation and oedema that are hallmark findings of TTS in the acute phase. Myocardial oedema is typically transmural in TTS and resolves within 6 months. CMR is also useful in the subacute phase to assess resolution of  regional dysfunction. Myocardial oedema and the absence of late gadolinium enhancement (LGE) in CMR can differentiate TTS from ACS and myocarditis and confirm the diagnosis of TTS. 

The presence of LGE in the acute phase is associated with increased risk of cardiogenic shock and delayed resolution of wall motion abnormalities. Ventricular and apical thrombi that cannot be detected through TTE, can be detected as low signal intensity without gadolinium uptake through early Gadolinium (EGE) sequences of CMR. A study including 148 patients with myocardial infarction and non-obstructed coronary artery disease (MINOCA), patients underwent CMR within 5 days of presentation and researchers found that 35% of patients had TTS without prior evidence of TTE or ventriculography. 

*Coronary angiography and ventriculography:

It is required to differentiate TTS and ACS. Most TTS patients have normal coronaries. There may be findings of atherosclerosis that do not match the degree of LV dysfunction or regional wall-motion abnormalities. Invasive assessment for the presence of a pressure-gradient in the outflow tract and the LV end-diastolic pressure (LVEDP) can be used. LVEDP is considered a good predictor for in-hospital complications. Although some suspected cases of ACS show normal coronary arteries on coronary angiography and one-third of TTS present with Apical MI, a diagnostic algorithm may help differentiate these cases. 

-Full recovery occurs within days to weeks in most cases.

-Mortality rate is higher in males especially if underlying critical illness exists.

-About 22% of patients will experience serious complications such as ACS. Subclinical cardiac dysfunction has been detected as a long-term consequence of TTS.

-Frequency of complications: 12-45% will experience acute heart failure, 10–25% LVOTO, 14–25% mitral regurgitation, 6–20% cardiogenic shock, 5–15% atrial fibrillation, 2–8% LV-thrombus, 4–6% cardiac arrest, 5% atrioventricular block. Other rare complications include 2–5% tachyarrhythmia, bradyarrhythmia and torsade de pointes, 1–4.5% death, about 3% ventricular tachycardia/fibrillation, and <1% acute ventricular septal defect.

-About 1.7% per patient-year is the risk of stroke or transient ischemic attack in TTS. It is recommended to apply CHA2DS2VASc score for prediction of cerebrovascular events and starting suitable anticoagulation even in absence of atrial fibrillation.

-An 3% absolute 6-year risk of heart failure hospitalization is noticed in TTS.

-Recurrence rate of TTS is about 4-5% within 3 weeks up to 4.7 years after the initial TTS episode.

-Annual recurrence rate of TTS is about 1-3.5%.

-Most TTS cases are hospitalized due to ACS suspicion. Due to the transient dysfunction that characterize TTS, treatment is mainly supportive and aims to prevent complications. Some of the medications used are angiotensin-converting enzyme (ACE) inhibitors,  angiotensin-receptor blockers (ARBs), antiplatelets and beta blockers (BB). 

-Anticoagulants like subcutaneous or intravenous heparin are given due to the risk of LV thrombus and its embolization. Oral anticoagulants can be given for 3 months. Continuous ECG for at least 48 hours is required to detect any arrhythmias.

-Any complication requires hospitalization in an intensive care unit.

-If patients had acute pulmonary oedema, intravenous diuretics and nitroglycerine are given after exclusion of LVOTO to avoid worsening of pressure gradient. 

-Hypotension without heart failure requires intravenous fluids, short-acting BB, up to LV assist device.

-ACE inhibitors or ARBs are given for at least 1 year to improve survival rate.

*Management of Cardiogenic Shock:

Cardiogenic shock is present in about 10% of cases and is associated with 5-fold higher mortality risk. It is necessary to identify the presence of LVOT obstruction through Doppler echocardiography or invasive angiography measuring the LVOT pressure gradients before starting the management of cardiogenic shock. The use of exogenous catecholamines is limited as TTs itself causes elevated levels of catecholamines. Patients with significant LVOT obstruction, it is contraindicated to use inotropes as they may worsen the degree of obstruction and shock. Diuretics, nitroglycerin or insertion of an intraaortic balloon pump should also be avoided. In this case, IV fluids and short-acting BB may improve cardiogenic shock and resolve the obstruction. Levosimendan which is a calcium sensitizer can be considered as well. Mechanical circulatory support through venoarterial extracorporeal membrane oxygenation is considered in patients with refractory LV obstruction and dysfunction.

*Management of Acute heart failure: 

ACEI or ARBs, BB  ± diuretics and nitroglycerin are used in acute heart failure to reduce ventricular filling pressures (in the absence of significant LVOT obstruction). BB can reduce the  effects of circulating catecholamines and prevent cardiac rupture. However, BB should be carefully used if bradycardia and a corrected QT interval (QTc) >500 ms due to risk of pause-dependent torsades de pointes (A fast and life-threatening form of ventricular tachycardia that can lead to ventricular fibrillation and cardiac arrest, when a pause occurs, a delayed repolarization provokes the arrhythmia).

*Management of LV thrombus formation:

Patients with severe LV dysfunction have a potential risk of  intraventricular thrombus formation and systemic embolisation. CMR or TTE should be used to evaluate the presence of LV thrombus. About 1-2% of TTS patients have complications with LV thrombus. However, it is not recommended to use prophylactic anticoagulation but used when there is a severe LV dysfunction. Duration of anticoagulation in TTS complicated with LV thrombus should be at least 3 months or until resolution of LV function.

*Management of life-threatening arrhythmias:

Life-threatening arrhythmias include severe bradyarrhythmias or ventricular tachycardia and ventricular fibrillation. About 3-8.6% of TTS cases may have ventricular tachycardia or ventricular fibrillation. A prolonged  corrected QT interval (QTc) exceeding 500 ms presents in most of the severe ventricular tachyarrhythmic cases. Magnesium sulfate and/or a short-acting BB are used for management of ventricular tachycardia. Direct current cardioversion is also used if there is a sustained, pulseless ventricular tachycardia. Temporary pacing (using external electrical impulses to maintain a stable heart rate and normal blood flow) should be considered in cases presenting with  torsades de pointes with QT interval prolongation and bradycardia. A permanent pacemaker implantation is considered when persistent high-grade atrio-ventricular block occurs. It is important to note that significant arrhythmias may persist during long-term follow-up.

*Long-term management:

Complete recovery of TTS may occur within a few days up to several weeks. Medical therapy through ACEI/ARB, BB, and if required diuretics, should be continued at least for 3 months or until resolution of LV function. According to the International Takotsubo Registry, using ACEI or ARBs improved the survival 1-year-follow up of TTS with less recurrence rate of TTS. If patients have co-existing coronary artery disease, aspirin and statins are considered for secondary prevention. If the underlying condition is  irreversible cardiomyopathy, heart failure medications are also considered. It is also to target the emotional stressors that could lead to recurrence of TTS.

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